Chemotherapeutic nucleosides that function as inhibitors of polymerases must be phosphorylated intracellularly by endogenous nucleoside kinases to their respective mono-, di- and tri-phosphate derivatives. Unfortunately, biological targets, such as the herpes-virus or tumor cells, can readily become resistant to these nucleosides by either altering or removing the nucleoside kinase responsible for mono-phosphorylation. For example, the efficacy of antiviral nucleosides against HIV is reduced in monocytes and macrophages, since they contain only low levels of nucleoside kinases. In addition, in quiescent lymphocytes, thymidine analogs, such as AZT, are poorly phosphorylated. Because of these concerns, a number of approaches have been developed for the delivery of mono- and diphosphorylated nucleosides.
Recently, several attempts have been made to increase the therapeutic index of AZT by delivering the phosphorylated compound in the form of a phosphate or phosphoramidate prodrug. In particular, due largely to their reduced cytotoxicity, hydrophobic alkyl and aryl triesters of glycine, alanine, leucine, and phenylalanine phosphoramidates of AZT are highly effective and selective inhibitors of HIV viral replication.
In spite of these efforts, a continuing need exists for chemotherapeutic agents with antiviral and or anticancer properties.
The present invention provides compounds that act as antiviral and or anticancer agents. Accordingly there is provided a compound of the invention which is a compound of formula I: 
wherein
R1 is hydrogen, halo, hydroxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyloxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, trifluoromethyl, or NRaRb;
R2 and R3 are each independently hydrogen, halo, hydroxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyloxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, trifluoromethyl, azido, cyano, or NRcRd;
R4 is hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, aryl(C1-C6)alkyl, or 2-cyanoethyl, wherein any aryl ring may optionally be substituted with 1, 2, or 3 halo, hydroxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyloxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, or amino;
R5 is an amino acid or a peptide;
X is oxy (xe2x80x94Oxe2x80x94) thio (xe2x80x94Sxe2x80x94) or methylene (xe2x80x94CH2xe2x80x94);
Ra and Rb are each independently hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, benzyl, phenethyl, or (C1-C6)alkanoyl; or Ra and Rb together with the nitrogen to which they are attached are pyrrolidino, piperidino or morpholino;
Rc and Rd are each independently hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, benzyl, phenethyl, (C1-C6)alkanoyl, xe2x80x94C(xe2x95x90O)N(Re)(Rf), or xe2x80x94C(xe2x95x90O)ORg; or Rc and Rd together with the nitrogen to which they are attached are pyrrolidino, piperidino or morpholino;
Re and Rf are each independently hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, benzyl, or phenethyl; or Re and Rf together with the nitrogen to which they are attached are pyrrolidino, piperidino or morpholino; and
Rg is hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, benzyl, or phenethyl;
or a pharmaceutically acceptable salt thereof.
The invention also provides a compound of formula I wherein R1-R4 have any of the values described herein, and wherein R5 is a nitrogen linked radical of formula III: 
wherein Rh is hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(C1-C6)alkyl, (C1-C6)alkyl-Sxe2x80x94)C1-C6)alkyl-, aryl, heteroaryl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl; wherein any aryl or heteroaryl may optionally be substituted with 1, 2, or 3 Z; Rj is hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(C1-C6)alkyl, phenyl, benzyl, or phenethyl; and wherein each Z is independently halo, hydroxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyloxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, or amino. Preferably, the carbon bearing Rh has the (S) configuration.
The invention also provides a compound of formula I wherein R1-R4 have any of the values described herein, and wherein R5 is a nitrogen-linked radical of formula VI: 
wherein Rah is hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(C1-C6)alkyl, (C1-C6)alkyl-Sxe2x80x94(C1-C6)alkyl-, aryl, heteroaryl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl; wherein any aryl or heteroaryl may optionally be substituted with 1, 2, or 3 Z; Rai and Raj are each independently hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(C1-C6)alkyl, phenyl, benzyl, or phenethyl; and each Z is independently halo, hydroxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyloxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, or amino. Preferably, the carbon bearing Rah has the (S) configuration.
The invention also provides a compound of formula II: 
wherein
R6 is adenine, guanine, cytosine, thymine, or uracil, optionally substituted by 1, 2, or 3 Y; wherein each Y is independently halo, hydroxy (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyloxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, trifluoromethyl, hydroxy(C1-C6)alkyl, xe2x80x94(CH2)1-4P(xe2x95x90O)(ORk)2 aryl, aryl(C1-C6)alkyl, or NRmRn, and wherein any aryl ring may optionally be substituted with 1, 2, or 3 halo, hydroxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyloxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, or amino;
one of R7 and R8 is xe2x80x94NR(Ro)C(xe2x95x90O)N(Rq), or xe2x80x94N(Ro)C(xe2x95x90O)ORr, and the other is hydrogen, halo, hydroxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyloxy, (C1-C6)alkanoyloxy, trifluoromethyl, azido, cyano, or RNsRt;
R9 is hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, aryl(C1-C6)alkyl, or 2-cyanoethyl, wherein any aryl ring may optionally be substituted by 1, 2, or 3 halo, hydroxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyloxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, or amino;
R10 is an amino acid or a peptide;
X is oxy, thio, or methylene;
each Rk is independently hydrogen or (C1-C6)alkyl;
Rm and Rn are each independently hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, benzyl, phenethyl, or (C1-C6)alkanoyl; or Rm and Rn together with the nitrogen to which they are attached are pyrrolidino, piperidino or morpholino;
Ro is hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, benzyl, or phenethyl;
Rp and Rq are each independently hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, benzyl, or phenethyl; or Rp and Rq together with the nitrogen to which they are attached are pyrrolidino, piperidino or morpholino; and
Rr is hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, benzyl, or phenethyl; and
Rs and Rt are each independently hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, benzyl, phenethyl, or (C1-C6)alkanoyl; or Rs and Rt together with the nitrogen to which they are attached are pyrrolidino, piperidino or morpholino;
or a pharmaceutically acceptable salt thereof.
The invention also provides a compound of formula V: 
wherein
R11 is adenine, guanine, cytosine, thymine, or uracil, optionally substituted by 1, 2, or 3 U; wherein each U is independently halo, hydroxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyloxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, trifluoromethyl, hydroxy(C1-C6)alkyl, xe2x80x94(CH2)1-4P(xe2x95x90O)(ORw)2 aryl, aryl(C1-C6)alkyl, or NRxRy;
one of R12 and R13 is azido and the other is hydrogen, halo, hydroxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyloxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, trifluoromethyl, azido, cyano, xe2x80x94N(Rz)C(xe2x95x90O)N(Raa)(Rab), xe2x80x94N(Rz)C(xe2x95x90O)ORac, or NRadRae;
R14 is hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, aryl, aryl(C1-C6)alkyl, or 2-cyanoethyl, wherein any aryl ring may optionally be substituted by 1, 2, or 3 halo, hydroxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyloxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, or amino;
R15 is an amino acid or a peptide;
W is oxy, thio, or methylene;
each Rw is independently hydrogen or (C1-C6)alkyl;
Rx and Ry are each independently hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, benzyl, phenethyl, or (C1-C6)alkanoyl; or Rx and Ry together with the nitrogen to which they are attached are pyrrolidino, piperdino or morpholino;
Rz is hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, benzyl, or phenethyl;
Raa and Rab are each independently hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, benzyl, or phenethyl; or Raa and Rab together with the nitrogen to which they are attached are pyrrolidino, piperidino or morpholino; and
Rac is hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenzyl, benzyl, or phenethyl; and
Rad and Rae are each independently hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, benzyl, phenethyl, or (C1-C6)alkanoyl; or Rad and Rae together with the nitrogen to which they are attached are pyrrolidino, piperidino or morpholino;
or a pharmaceutically acceptable salt thereof.
The invention also provides a compound of formula VII: 
wherein
R16 is adenine, guanine, cytosine, thymine, 3-deazaadenine, or uracil, optionally substituted by 1, 2, or 3 U; wherein each is independently halo, hydroxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyloxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, trifluoromethyl, hydroxy(C1-C6)alkyl, xe2x80x94(CH2)1-4P(xe2x95x90O)(ORw)2 aryl, aryl(C1-C6)alkyl, or NRxRy;
one of R17 and R18 is hydroxy and the other is hydrogen, halo, hydroxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyloxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, trifluoromethyl, azido, cyano, xe2x80x94N(Rz)C(xe2x95x90O)N(Raa)(Rab), xe2x80x94N(Rz)C(xe2x95x90O)ORac, or NRadRae;
R is hydrogen, (Cxe2x80x94C)alkyl, (Cxe2x80x94C)cycloalkyl, aryl, aryl(C-C6)alkyl, or 2-cyanoethyl, wherein any aryl ring may optionally be substituted by 1, 2, or 3 halo, hydroxy, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyloxy, (C1-C6)alkanoxy, (C1-C6)alkanoyloxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, or amino;
R20 is an amino acid or a peptide;
W is oxy, thio, or methylene;
each Rw is independently hydrogen or (C1-C6)alkyl;
Rx and Ry are each independently hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, benzyl, phenethyl, or (C1-C6)alkanoyl; or Rx and Ry together with the nitrogen to which they are attached are pyrrolidino, piperdino or morpholino;
Rz is hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, benzyl, or phenethyl;
Raa and Rab are each independently hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, benzyl, or phenethyl; or Raa and Rab together with the nitrogen to which they are attached are pyrrolidino, piperdino or morpholino; and
Rac is hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, benzyl, or phenethyl; and
Rad and Rae are each independently hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, benzyl, pheneyl, or (C1-C6)alkanoyl; or Rad and Rae together with the nitrogen to which they are attached are pyrrolidino, piperidino or morpholino;
or a pharmaceutically acceptable salt thereof.
The invention also provides a compound of formula II wherein R6-R9 have any of the values described herein, and wherein R10 is a nitrogen linked radical of formula III as described hereinabove.
The invention also provides a compound of formula V wherein R11-R14 have any of the values described herein, and wherein R15 is a nitrogen linked radical of formula III as described hereinabove.
The invention also provides a compound of formula VII wherein R16-R19 have any of the values described herein, and wherein R20 is a nitrogen linked radical of formula III as described hereinabove.
The invention also provides a compound of formula II wherein R6-R9 have any of the values described herein, and wherein R10 is a nitrogen linked radical of formula VI as described hereinabove.
The invention also provides a compound of formula V wherein R11-R14 have any of the values described herein, and wherein R15 is a nitrogen linked radical of formula VI as described hereinabove.
The invention also provides a compound of formula VII wherein R16-R19 have any of the values described herein, and wherein R20 is a nitrogen linked radical of formula VI as described hereinabove.
The invention also provides a pharmaceutical composition comprising a compound of formula I, formula II, formula V, or formula VII, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier.
Additionally, the invention provides a therapeutic method for preventing or treating a viral infection comprising administering to a mammal in need of such therapy, an effective amount of a compound of formula I, formula II, formula V, or formula VII (preferably a compound of formula I or formula II); or a pharmaceutically acceptable salt thereof.
The invention also provides a composition of matter comprising a compound of formula I, formula II, formula V, or formula VII (preferably a compound of formula I or formula II); or a pharmaceutically acceptable salt thereof and a reagent (e.g. a peptide, a saccharide, a polyclonal antibody, a monoclonal antibody) that is capable of targeting the compound to a virus.
The invention also provides a composition of matter comprising a compound of formula I, formula II, formula V, or formula VII (preferably a compound of formula V or formula VII); or a pharmaceutically acceptable salt thereof and a reagent (e.g. a peptide, a saccharide, a polyclonal antibody, a monoclonal antibody) that is capable of targeting the compound to a tumor or cancer cell.
The invention provides a compound of formula I or formula II for use in medical therapy (preferably for use as an antiviral agent or for use in treating HIV), as well as the use of a compound of formula I or formula II for the manufacture of a medicament for the treatment of a pathological condition or symptom associated with viral infection (e.g. HIV) in a mammal, such as a human.
The invention provides a compound of formula V or VII for use in medical therapy (preferably for use as an anticancer or antitumor agent), as well as the use of a compound of formula V or VII for the manufacture of a medicament for the treatment of a pathological condition or symptom associated with cancer (e.g. a cancerous tumor) in a mammal, such as a human.
The invention also provides processes and novel intermediates disclosed herein that are useful for preparing compounds of formula I, formula II, formula V, and formula VII. Some of the compounds of formula I, formula II, formula V, or formula VII are useful to prepare other compounds of formula I, formula II, formula V, or formula VII.
The invention also provides a therapeutic method comprising treating breast cancer by administering to a mammal in need for such therapy, an effective amount of a compound of formula VII or a pharmaceutically acceptable salt thereof.